This proposal aims to characterize the role of the tumor suppressor protein PML in the regulation of metabolic processes, and the consequences of PML-loss in obesity, diabetes and cancer pathogenesis. The relevance of this study relies in the possible utilization of PML as a marker of metabolic diseases and target for therapy. We have cloned, characterized and identified PML, throughout the years, as a tumor suppressor frequently loss in blood and solid cancers. PML exerts its tumor suppressive activity through the regulation of senescence, apoptosis and neoangiogenesis. Surprisingly, a detailed analysis of the metabolic status of Pml-deficient mice and cells has unveiled a novel role for PML in the regulation of metabolism, which shows that Pml-loss results in altered energy source utilization, defective response to fasting, and reduced fatty acid oxidation. Preliminary data show that PML is required for proper AMPK activation, and for the response of mice to the antidiabetic drug Metformin. Additionally, cytoplasmic PML localization increases upon energy deprivation, thus suggesting that PML function is modulated according to the demand of energy. The notion of cancer genes directly regulating metabolic processes has been supported by the recent identification of tumor suppressors and oncogenes at the crossroad of metabolism and cancer, such as p53 and Myc. Hence, a metabolic function for PML becomes extremely attractive, not only in terms of metabolic diseases per se, but also in the context of cancer susceptibility. This application is based on the hypothesis that PML in the cytoplasm is required for the proper metabolic function of the cell and that, in turn, adequate metabolic regulation by PML is a key component for its tumor suppressive activity. We will address this hypothesis with the following specific aims: (1) To define the role of PML in nutrient adaptation and analyze the status of PML in obese and diabetic patients; (2) to assess the molecular mechanism of AMPK regulation by PML and the consequences of Pml-loss in metabolic pathways; (3) to ascertain the regulation and metabolic function of PML in the cytoplasm and (4) to study the implications of PML metabolic function on in its tumor suppressive activity in vivo.